Chemotherapy has made a significant impact on the longevity and quality of life of those affected by cancer. The influence a drug may have on the outcome of cancer treatments, however, is highly dependent on the ability of the therapeutic to selectively and effectively kill targeted malignant cells while leaving normal cells untouched. Addressing this challenge has been a central focus for the discovery of new therapeutics that can alter specific biological processes that are critical to the survival of cancer cells. New methods of administering drugs (i.e., orally, systemically, or loco-regionally) also plays a critical role in the development of new treatment strategies for effective management of cancer. [10-16] Although a number of small molecules are known to have potent cytotoxicity towards cancer cells, relatively few anticancer agents are used clinically due, in part, to low therapeutic windows for drug efficacy compared to drug-related toxicity.[17] Drug delivery systems (DDSs) have, therefore, attracted wide attention in cancer research due to their potential to significantly reduce the toxicity of anticancer agents in normal healthy tissues, while making it possible to control the concentration and location of active drugs released in the body over long periods of time.[18] DDSs may also be used to increase the potency of drugs by increasing their accumulation at targeted tissues compared to administration of equitoxic levels of free drugs in solution.[19, 20]
DDSs have already been shown to play a critical role in the development of effective therapeutic strategies against several forms of cancer.[21] Nanoparticle carriers, for instance, are useful as systemically-administered delivery vessels for cancer therapeutics to solid tumors[22-26] due to their enhanced permeability from leaky blood vessels in tumor tissues compared to blood vessels in healthy tissues.[27-29]
An important issue in determining the effectiveness of a DDS is the ability to control the location and time over which active drug release occurs. This challenge has motivated the development of methods to trigger the release drug loads from DDSs upon arrival at the target site. The use of heat [37], light [38], or ultrasonic radiation [39, 40], for example, has been reported to trigger the release of encapsulated drugs from DDSs. Although these triggering methods show promise for the treatment of some forms of cancer, the requirement of external stimuli to catalyze the local release of drugs may limit these therapeutic approaches to certain areas of the body (e.g., the extremities). Another valuable approach for triggering the release of therapeutics from DDSs for the treatment of cancer could be to exploit differences in the natural physiological environment of tumors compared to normal tissues. Differences in acidity, for instance, are particularly interesting as a stimulus to distinguish between normal and malignant tissues since it is well documented that the extracellular pH of many tumors is slightly more acidic than the blood or normal tissues.[31, 41-43] In addition, the endocytosis of polymers and nanoparticles by tumor cells has also been observed;[44] endocytosis is expected to deliver DDSs to endosomes and lysosomes, the pH of which is 2 orders of magnitude lower than plasma pH.
Among the many challenges in engineering effective cancer drug delivery systems is the development of simple methods to incorporate large loads of therapeutic agents to the delivery vessels that are released in active form primarily at the targeted site. Previously reported delivery vessels, mostly polymer-based, are often designed to display the controlled release of active agents via dissolution, matrix degradation, diffusion, or cleavage of covalently-attached prodrugs.[21] Organic functional groups that decompose slowly in an aqueous environment have attracted wide interest as potential linkers for the covalent conjugation of drugs to polymers for a range of drug delivery applications. [43, 45-50]
Recent findings suggest that a promising strategy for developing effective DDSs is to covalently attach therapeutics to delivery vessels via acid-sensitive linkers.[20, 30, 31] The improved in vivo efficacy for the treatment of solid tumors using acid-sensitive linkers in polymer-based drug delivery systems compared to administration of free drug in solution encourages the development of new general methods to exploit acid-catalyzed activation to control the release of a broad spectrum of potent cytotoxic agents from polymeric DDSs. Drug delivery systems have also included the encapsulation of drugs non-covalently in carriers that are preferentially released in an acidic environment. An ethyoxyethyl protecting group for imidazoles was shown to be hydrolytically unstable in aqueous acidic conditions at elevated temperatures. [69]
Other linking systems explored by researchers include, for example, the covalent conjugation of drugs via linkers that are cleaved by disease specific enzymes, or linkers that are sensitive to oxygen levels.
New strategies for preparing DDSs that are capable of retaining high loads of cancer therapeutics and selectively releasing them in a targeted tissue will help ameliorate many of the current problems in chemotherapy.
Although several acid-sensitive linkers have been reported for conjugation of certain classes of small molecule cytotoxic agents to polymers,[45-50] there is a need for linker systems that have the advantages of: 1) facile attachment of a broad range of cytotoxic agents to drug delivery carriers; 2) tunable rates of cleavage under mild aqueous acidic conditions for exploring optimal rates of drug release for, for example, cancer therapy; and 3) adaptability for conjugating drugs to a range of drug delivery carriers. These advantages will provide a means to rapidly synthesize a range of e.g., polymeric drug delivery systems carrying a variety of therapeutic agents that can be release from the polymers at controlled rates in a tumor-specific environment. The utility of acid-sensitive linkers is not limited to the delivery of drugs for cancer treatment. Other areas where tunable acid-sensitive linkers may be useful include therapeutics for non-cancerous conditions, and the delivery of compounds other than therapeutics, such as, for example, imaging agents.